Indication: For the treatment of Clostridium difficile-associated diarrhea (CDAD).

Pharmacology: Fidaxomicin is a fermentation product from the actinomycete Dactylosporangium aurantiacum. It is bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases.

Clinical trials: In two randomized, double-blind trials, a noninferiority design was utilized to demonstrate the efficacy of fidaxomicin (200 mg b.i.d. for 10 days) compared to vancomycin (125 mg four times daily for 10 days) in adults with CDAD. Enrolled patients received no more than 24 hours of pretreatment with vancomycin or metronidazole.

CDAD was defined by more than three unformed bowel movements (or >200 mL of unformed stool for subjects having rectal collection devices) in the 24 hours before randomization and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization. Enrolled patients had either no prior CDAD history or only one prior CDAD episode in the past three months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.

The primary efficacy endpoint was the clinical response rate at the end of therapy, based on improvement in diarrhea or other symptoms such that, in the investigator's judgment, further CDAD treatment was not needed. An additional efficacy endpoint was sustained clinical response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment. Sustained response was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment.

The results for clinical response at the end of treatment in both trials indicate that fidaxomicin is noninferior to vancomycin (Trial 1: fidaxomicin 88% vs. vancomycin 86%; Trial 2: fidaxomicin 88% vs. vancomycin 87%). The results for sustained clinical response at the end of the follow-up period indicate that fidaxomicin is superior to vancomycin on this endpoint (Trial 1: fidaxomicin 70% vs vancomycin 57%; Trial 2: fidaxomicin 72% vs. vancomycin 57%). Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in patients taking fidaxomicin.

Restriction endonuclease analysis was used to identify C. difficile baseline isolates in the BI group, isolates associated with increasing rates and severity of CDAD in the years prior to the clinical trials. Similar rates of clinical response at the end of treatment and proven or suspected CDAD during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients infected with a BI isolate.

However, fidaxomicin did not demonstrate superiority in sustained clinical response when compared with vancomycin.

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